Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus.

Maternal diabetes constitutes an unfavorable intrauterine environment for offspring development. Although it is known that diabetes can cause brain alterations and increased risk for neurologic disorders, the relationship between neuroimmune activation, brain changes, and neurodevelopment deficits in the offspring remains unclear. In order to elucidate the short- and long-term biological basis of the developmental outcomes caused by the severe uncontrolled maternal hyperglycemia, we studied apoptosis, neurogenesis, and neuroinflammation pathways in the hippocampus of neonates and young rats born to diabetic dams. Diabetes was induced on gestational day 5 by an injection of streptozotocin. Evaluations of milestones, body growth, and inhibitory avoidance were performed to monitor the offspring development and behavior. Hippocampal modifications were studied through cellular survival by BrdU in the dentate gyrus, expression of apoptosis-regulatory proteins (procaspase 3, caspase 3, and Bcl-2), BDNF, and neuroinflammatory modulation by interleukins, MHC-I, MHC-II, Iba-1, and GFAP proteins. Severe maternal diabetes caused microsomia and neurodevelopmental delay in pups and decrease of Bcl-2, procaspase 3, and caspase 3 in the hippocampus. Moreover, in a later stage of development, it was found an increase of TNF-α and a decrease of procaspase 3, caspase 3, MHC-I, IL-1ß, and BDNF in the hippocampus, as well as impairment in cellular survival in the dentate gyrus. This study showed significant short- and long-term commitments on the development, apoptosis, cell survival, and neuroinflammation in the offspring hippocampus induced by severe uncontrolled maternal hyperglycemia. The data reinforce the need for treatment of maternal hyperglycemic states during pregnancy and breast-feeding.

Paternal physical exercise demethylates the hippocampal DNA of male pups without modifying the cognitive and physical development.

Maternal exercise is known to have beneficial effects in progeny development, but the influence of paternal exercise on the offspring still unclear. Since spermatogenesis is a continuous process, the father's life experiences can reprogram epigenetic content of the sperm and somehow interfere on offspring phenotype. This study was designed to evaluate the effects of paternal physical exercise on cognitive and physical development and on hippocampal DNA methylation levels of the offspring. Adult male Wistar rats were divided into two groups: sedentary and exercised. The exercise protocol occurred before mating and consisted of treadmill running, 5 consecutive days/week for 8 weeks (20 min/day). The mothers were not trained. The following developmental parameters were examined in male offspring: body growth, physical and cognitive performance, weights of adrenal glands, gonadal fat and hindlimb muscles, BDNF expression and global DNA methylation at the hippocampus. The progeny of trained and sedentary fathers did not differ in relation to physical parameters and performance, spatial memory and BDNF expression. However, paternal exercise promoted a decrease in offspring´s relative gonadal fat weight and a lower percentage of global hippocampal DNA methylation compared to offspring of sedentary fathers. These results pointed to interference of male physical activity at the time of conception on adiposity and hippocampal epigenetic reprogramming of male offspring. The data reinforces that exercise does not harm the descendant's development and emphasize the benefits to include the practice of physical exercise in a healthier lifestyle of the parents. Nevertheless, future studies are necessary and should investigate further the long-effects of epigenetic mechanisms in order to elucidate the father's contribution in fetal programming.